Genetic variation near GRB2 and KCNB2 identified by a genome-wide association study are reproducibly associated with Diabetic Retinopathy

Georgia Kaidonis, Jamie Craig, Rhys Fogarty, Mark Gillies, Weiyong Shen, Shiwani Sharma, Binoy Appukuttan, Bishwanath Pal, Periasamy Sundaresan, Kathryn Burdon

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    Purpose: Diabetic Retinopathy (DR) is a blinding complication of type 2 diabetes (T2D) with evidence for genetic susceptibility. We conducted a well powered genome-wide association study (GWAS) to identify susceptibility loci for DR, focusing on sight-threatening disease, with three independent replication cohorts.

    Methods: A GWAS using the OmniExpress array (Illumina) was conducted in 1090 samples collected from Caucasians with type 2 diabetes (T2D) recruited from multiple hospitals. Following data cleaning, association analysis was performed for 397 cases with sight threatening DR (proliferative DR, severe non-proliferative DR, or clinically significant macular edema) and 561 controls with diabetes but no DR, plus each DR subtype alone and combined (Any DR), compared with controls. Top ranking SNPs were genotyped in two Caucasian replication cohorts, one with T2D and the other with type 1 diabetes (T1D). Two replicated SNPs were typed in a further replication cohort of Indian T2D patients from Aravind Eye Hospital, India.

    Results: SNP rs783992 near KCNB2 (voltage gated potassium channel, Kv2.2), was associated with any DR (p=2.01x10-8) and proliferative DR (p=7.5x10-8) and also showed replication in the Causcasian T2D cohort (p=0.01, OR[95%CI]=1.33[1.07-1.66]), but not in the Indian or T1D cohorts. SNP rs9896052 near GRB2 (Growth factor receptor-bound protein 2, an adaptor protein involved in signal transduction/cell communication) was associated with sight-threatening DR (p=4.71x10-8) and macular edema (p=1.0x10-6) and showed replication in the Caucasian T2D (p=0.035, OR[95%CI]=1.45[1.03-2.18]), the T1D (p=0.048, OR[95%CI]=1.54[1.00-2.36]) and the Indian T2D (p=0.016, OR[95%CI]=1.47[1.07-2.02]) cohorts. Immunohistochemical labelling showed expression of GRB2 in both human and mouse retina, and retinal expression was increased in response to diabetes and retinal stress in Akita diabetic mice.

    Conclusions: SNPs rs783992 and rs9896052 are reproducibly associated with DR in Caucasians with T2D and rs9896052 is also more broadly associated in other populations. This is the first GWAS for DR to provide genome-wide significant association with replication.
    Original languageEnglish
    Article number2267560
    Pages (from-to)2237
    Number of pages1
    JournalInvestigative Ophthalmology and Visual Science
    Issue number13
    Publication statusPublished - Apr 2014


    • meeting abstract
    • diabetic retinopathy
    • genetic variants


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